Abstract

Desmoid tumors (DTs) are nonmalignant neoplasms of mesenchymal origin that mainly contain fibroblast lineage cells. These tumors often occur in Familial Adenomatous Polyposis Coli (FAP) patients who have germline mutations in the APC gene. Given emerging data that has implicated multipotent mesencyhmal stromal cells (MSCs) in the origin of mesenchymal tumors, we hypothesized that DTs may arise in FAP patients after MSCs acquire somatic mutations during the proliferative phase of wound healing. To test this idea, we examined 16 DTs from FAP-associated and sporadic cases, finding that all 16/16 tumors expressed stem cell markers whereas matching normal stromal tissues were uniformly negative. DTs also contained a subclass of fibrocytes linked to wound healing, angiogenesis and fibrosis. Using a MSC cell line derived from a FAP-associated DT, we confirmed an expected loss in the expression of APC and the transcriptional repressor BMI-1 while documenting the co-expression of markers for chondrocytes, adipocytes and osteocytes. Together, our findings argue that DTs result from the growth of MSCs in a wound healing setting that is associated with deregulated Wnt signaling due to APC loss. The differentiation potential of these MSCs combined with expression of BMI-1, a transcriptional repressor downstream of Hedgehog and Notch signaling, suggests that DTs may respond to therapies targeting these pathways.